JPH07501320A - Treatment of ocular fibrosis with interferon alpha - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Technical field for the treatment of ocular fibrosis using interferon alpha The present invention relates to various eye diseases and the various forms that occur in and around the eyes due to ophthalmological procedures. The present invention relates to the use of topical interferon-alpha in the treatment of fibrosis. present invention Especially after photoablative refractive keratectomy (PRK) using a laser beam. Concerning the reduction of corneal scars. In addition, crystalline crystals after true cataract surgery due to artificial lens implantation Relating to reducing opacity in the posterior part of the body and reducing wound scars after glaucoma filtration surgery.

Interferon-α is also used to coat the implanted artificial lens before and during implantation. It will be done. In addition, intraocular injection during eye surgery can prevent post-opacification after cataract surgery and intravitreal injection. Prevention of retinal fibrosis and proliferative vitreoretinopathy by injection, glaucoma filtration by supraconjunctival injection It is also possible to prevent fibrosis and scarring after excessive surgery.

Background technology In the field of ophthalmic surgery, photoablation using excimer and laser beams Refractive keratectomy removes the cornea of the eye and treats refractive errors (e.g., nearsightedness) and It is known to alleviate pathological conditions such as corneal diseases. Especially 193 nm fluoride The Rougon excimer laser beam destroys surrounding tissue by photoablation. Only the corneal tissue can be removed without causing burns.

Particularly important is the activation of corneal stromal cells when a wound occurs in the stroma. It is. As is well known, the basic response of injured tissue is to repair the defect. Therefore, the surgeon using this technique must understand the biochemistry of the wound itself and the healing phenomenon. , will face alterations in morphological features as well as tissue function.

Therefore, the excimer, laser beam, and abrane cone in the corneal tissue reach the surrounding area. Although it is an effective method of removing tissue with minimal damage to the The healing process does not necessarily lead to preservation of transparent corneal tissue.

Traditional methods to overcome this problem include prednisolone, prednisolone acetate , sodium prednisolone phosphate, fluorometalone, fluorometalone acetate , hydromesterone, dexamethacin, dexamethacin/alcohol, etc. Application of steroids. Other tested compounds include idoxuridine collagen bridges. mitomycin C, a binding inhibitor.

One of the objectives of the present invention is to investigate the wound repair mechanism after photoablative refractive keratectomy. The aim is to improve the known shortcomings of current procedures.

Interferons belong to a group of heterogeneous proteins that inhibit pleiotropic fibrotic responses. in Terferon originally has the ability to suppress the production of viral RNA and proteins. Although it is well known, it also has the effect of suppressing cell proliferation, and this is due to c-my This appears to be due to its ability to suppress the c proto-oncogene. Type 1 Inter -feron (viral suppressor interferon, interferon-alpha and -beta) ) is produced in response to bacterial infection, and the second type (immune interferon, interferon) is produced in response to bacterial infection. eron-γ) in response to specific antigens or mitogens (mitogens). produced. Among the various classes, α-interferon is produced by leukocytes, β-interferon is produced by fibroblasts, and γ-interferon is produced by activated phosphorus. secreted by the paraglobules. Interferon, especially interferon-α, is It has been used in the treatment of systemic malignant diseases in humans for the past 20 years with good results.

Recent advances in the treatment of fibrosis such as systemic sclerosis, pulmonary fibrosis, and keloids There is a lot of interest in Feron's potential. When fibroblasts are stimulated, Tarleukin-1-(IL-1), platelet-derived growth factor (PDGF), tumor necrosis interferon by numerous wound healing mediating cytokines such as death factor (TNF). is produced. Interferon stimulates fibroblast chemotaxis and proliferation and antigen production. The latter has a synergistic effect with TNF-α.

When a foreign body is implanted into the peritoneal cavity of a mouse, it becomes encapsulated in the presence of interferon-γ. It's no longer faint. That is, the collagen within this capsule was reduced. fibroblast glyco Saminoglycan production is suppressed by interferon-α, whereas collagen On the contrary, production increases. Inactivation of such activated fibroblasts results in a short-term interface. It persists for a long time after exposure to Elon. Among various interferons, α- and β - The subclasses exhibit a broad anti-fibrotic spectrum.

The present inventors demonstrated that bacterial interferon-α is associated with fetal calf serum and platelet-derived growth factor. Inhibition of in vitro proliferation of human thigh capsule fibroblasts derived from offspring Proven. The present inventors have shown that interferon is particularly useful in the treatment of fibrosis after PRK. We believe this may prove effective in treating ocular fibrosis and ocular fibrosis in general. Ru.

Disclosure of invention According to a first embodiment of the present invention, the cornea of a patient in need of treatment for corneal scarring is An effective dose of interferon-alpha or interferon-alpha that is pharmacologically acceptable. Preparations for treating corneal scars in patients, including carriers, diluents and/or excipients that can Techniques for administering drug components are provided.

According to a second embodiment of the invention, true cataract surgery for a patient in need of true cataract surgery Administer an effective amount of intercalary into the patient's lens capsule to prevent subsequent posterior opacification. A procedure for administering feron-α or interferon-α for the procedure Administering formulation components including pharmacologically acceptable carriers, diluents and/or excipients techniques are provided.

According to a third embodiment of the invention, treatment for patients in need of glaucoma filtration surgery is provided. Administer an effective amount under the patient's conjunctiva to prevent post-operative wound fibrosis and scarring. Procedures such as administering interferon-alpha or interferon-alpha or For such procedures, including pharmacologically acceptable carriers, diluents and/or excipients. Procedures such as administering the formulation components are provided.

According to a fourth embodiment of the invention, after retinal detachment surgery and/or vitrectomy, After trauma and due to retinal vascular disease (including diabetes, thalassemia, and retinal vein occlusion) This is a procedure to prevent the formation of both retinal membranes and proliferative vitreoretinopathy. Therefore, an effective amount of interferon-α should not be administered to the vitreous body or retina of patients with the disease. and interferon-alpha and pharmacologically acceptable carriers, diluents and/or excipients. Formulation components for the procedure are provided, including excipients.

In the present invention, interferon-α2A, interferon-α2B, Interferon-α2C and other interferon-α can be used. Ru.

The present invention also provides biodegradable polymers such as sebacic acid and bisparacarboxylic acid. Polymeric ester (polyanhydrin) that is a copolymer with phenokinobutane Providing a new protein formulation using poly(ortho)ester as a carrier or excipient. It is something to do.

The method of the present invention includes photoablative refractive keratectomy, lamellar keratoplasty, and lamellar keratectomy. To evaluate the scarring reaction after various corneal procedures such as corneal removal, corneal transplantation, pterygium removal and corneal curvature formation. prevent.

The subjects to which the methods according to the invention are applied are mainly humans.

However, these techniques (methods) can also be applied to other animals. Dew.

Additionally, the method of the present invention can prevent scarring after chemical damage to the conjunctiva and cornea. , also scarring conjunctivitis, Steve & Johnson syndrome, simplex & It can prevent scarring in pathological conditions such as Star keratitis. Ru. Furthermore, ocular fibrosis in thyroid eye disease, orbititis pseudotumor, orbital myositis, etc. It can also be prevented.

Topical compound thinners include Intron A powder (Schering-Plough) or Loefferon. Prepare A (Roche) as a 1 x 10' 10/+nl solution.

The formulation of Intron A is as follows. That is, α-2b interferon solution, United States Pharmacopoeia Anhydrous Dibasic Sodium Phosphate, United States Pharmacopoeia Sodium Phosphate Hydrate, European Pharmacopoeia glycine, European Pharmacopoeia Human Albumin Solution, European Pharmacopoeia Water for Injection.

The extractant may be hybromellose or polyvinyl alcohol, which is mixed with 1061U/ Dilute to ml.

The composition of the invention can be used as a solution, ointment, or as a collagen shield or conventional of non-toxic, pharmacologically acceptable carriers, diluents and/or excipients. May be administered topically in a similar dissolvable corneal contact dressing or by direct injection. You may shoot.

The dosage of interferon-α is 50,000 to 50 x 10' 1010. It may be 1 ml or about 1 x 10@-20 x lO'lU/ml.

Preferably the dose is between about 1 x 10' and about 10 x 10' lU/mI! shall be. stomach Interferon-α can be administered at 50 μl four times a day for six consecutive weeks.

Alternatively, it is preferably administered twice daily for one week. Also interferon- α is administered twice a day for 3 days or one drop every hour for 3 days. You may. This dosage applies to the first, second and third embodiments of the invention. I can do it.

When applied according to the fourth embodiment, interferon-α is administered at a dose of 5 Intravitreal within the range of 0,000 to 5.0 x 10' IUlo, 1 rnl Inject.

The compositions of the invention may also contain slow-release polymers. pharmacological Acceptable carriers, diluents and/or excipients include those well known in ophthalmic surgery, such as: It contains the following. i.e. hydroxyethyl cellulose, hibromero base, polyvinyl alcohol, gelatin, polyquad, dextran, castor oil or other vegetable oil (e.g. sesame oil), inert white soft paraffin, liquid paraffin Anhydrous lanolin, sodium hyaluronate, methylcellulose, potassium sorbate boric acid, sodium chloride, buffer salts in polysorbate, or pure water Acid bicarbonate, sodium citrate (citric acid). Also, these things are raw Biodegradable polymer esters (polyanhydrins), e.g. It may also be sebacic acid or paracarboxyphenoxybutane.

The compound also contains thiomersal, phenymercuric acetate, and benzyl alcohol chloride. Nitrium, sodium edetate, sodium metabisulfite, polymercuric nitrate, chloro Butol, Hyloxabol, Vorividone (Povidone), Propyl Hydroxybane It may also contain preservatives and fungicides such as fragrant acid and methylhydroxybenzoic acid. .

The composition of the present invention can be removed immediately after photoablative refractive keratectomy (PRK); Preferably, it is administered as an ointment, collagen shield, etc. interface If Ron is administered as a depletion drug, it should be administered 4 to 8 times a day for up to about 6 weeks. It is desirable to see it.

Corneal response can be controlled by treatment with interferon-α drops before PRK surgery You can. In addition, it is possible to adjust it even if you treat it with steroids in advance. Ru.

Interferon-α can be prepared from natural sources or by recombinant DNA techniques. It may be manufactured. All of these techniques are well known to those skilled in the art. .

BEST MODE FOR CARRYING OUT THE INVENTION Interface to prevent corneal scars after photoablative refractive keratectomy An effective amount of Elon-α-2b is administered topically to the postoperative cornea.

The present invention will be explained with reference to the following examples, but these examples do not fall within the scope of the invention. shall not be considered as limiting.

Example 1 Preparation of Interferon-alpha-2B Topical Compound The preparation of topical compound elimination includes Ron A powder (Schiering-Plough) is used as the base material, and this is 1 x to' 10/n+j! Make a solution of

Intron A formulations include: That is, α-2b interferon solution, United States Pharmacopoeia Anhydrous Dibasic Sodium Phosphate, United States Pharmacopoeia Sodium Phosphate Hydrate, European Pharmacopoeia glycine, European Pharmacopoeia Human Albumin Solution, European Pharmacopoeia Water for Injection.

The erasing substrate is hybromellose or polyvinyl alcohol, which is 10'1 Dilute to 0.07ml.

Example 2 The composition of the present invention can be removed immediately after photoablative refractive keratectomy (PRK); Administer as ointment, collagen shield, etc.

When interferon is given as a depletion drug, it can be administered at 4 doses per day for up to about 6 weeks. It is recommended to apply the eye drops once at a time.

Corneal reactions can be treated with interferon-α-2b drops before PRK surgery. It can be adjusted by Also, it can be adjusted even if the steroid is fully treated. It is.

Industrial applicability It is clear that the treatment method of the present invention can be used in a wide range of veterinary and medical fields. I have to.

The foregoing descriptions merely indicate some of the embodiments of the present invention and do not depart from the scope of the present invention. It will be obvious to those skilled in the art that improvements can be made to this without departing from the It's a white thing.

Reference materials Given V IK (1990), Ophthalmology Record Collection, 1081539° Syntron C ( 1990), Ophthalmology Record Collection, 1081540° Binder PS (1990), Ophthalmology Record Collection, 1081541゜International Survey Report 1゜ltvml:. . Plow on the convex part ne.

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Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MR, LK, LU, M G, MN, MW, NL, No, PL, RO, RU, SD, SE , UA, US (72) Inventors Gillies, Mark Settling Australia Australia, New South Wales, 2031, Landvwick, Warataos Tralia, New South Wales, 2030, Watson's Pay, Bell ・Australia, Australian Capital Territory 2604, NA Lavander, 46 Green Street

Claims (22)

[Claims] 1. Wound line after glaucoma filtration surgery to prevent opacification of the capsule after extracapsular cataract surgery To prevent fibrosis and scarring or the formation of preretinal membranes and proliferative vitreoretinopathy The use of interferon-alpha for the treatment of corneal scarring, with the aim of preventing corneal scarring. for. 2. The use according to claim 1, wherein the dose of interferon-α is about 5 0,000 to 50 x 106 IU/ml. 3. The use according to claim 2, wherein the dosage unit is about 1 x 106 to 20 ×106IU/ml. 4. The use according to claim 3, wherein the dosage range is from about 1 x 10 to about 10 ×106IU/ml. 5. Use according to any one of claims 1 to 4, wherein Interferon-α-2A is terferon-α. 6. Use according to any one of claims 1 to 4, wherein Interferon-α-2B is terferon-α. 7. Use according to any one of claims 1 to 4, wherein Interferon-α-2C is terferon-α. 8. Formulations interferon-alpha and pharmacologically acceptable carriers, diluents and/or or excipients. 9. The process of claim 8, comprising: said carrier, diluent and/or excipient; The excipient is a polymer that can be degraded in the living body. 10. The process of claim 9, wherein the biodegradable polymer is a polymer. Ester (polyanhydrin) or poly(ortho)ester. 11. The process of claim 10, wherein the polyanhydrin is sebacified. A copolymer of carbonic acid and bisparacarboxyphenoxybutane. 12. A method for treating corneal scars for a patient who requires corneal scar treatment, the patient interferon-alpha and a pharmacologically acceptable carrier, diluent and/or administration of interferon-alpha or synthetic preparations for corneal scar treatment containing or excipients. Something that includes giving. 13. For patients who require treatment to prevent capsule opacification after extracapsular cataract surgery, A method for preventing opacification of the posterior capsule after external cataract surgery, the method comprising: The membrane is coated with an effective amount of interferon-α or interferon-α in a pharmacologically acceptable manner. synthetic preparations for the method containing acceptable carriers, diluents and/or excipients; including administering a drug. 14. For patients requiring treatment to prevent wound fibrosis and scarring after glaucoma filtration surgery. A method for preventing wound fibrosis and scarring after glaucoma filtration surgery for patients. An effective amount of interferon-α or interferon-α and pharmacological administration under the conjunctiva Compounds for the method containing carriers, diluents and/or excipients acceptable to Involves administering a synthetic preparation. 15. A method according to any one of claims 12 to 14, comprising: The dose range for interferon-α is approximately 50,000 to 50 x 106 IU/ml. What to do. 16. 16. A method according to claim 15, wherein the dosage unit comprises about 1 x 106 - 20 x 106 IU/ml. 17. 17. A method according to claim 16, wherein the dose range is from about 1 x 106 to About 10 x 106 IU/ml. 18. A method according to any one of claims 14 to 17, Approximately 50μ of the interferon-α can be administered four times a day for six weeks. . 19. A method according to claim 18, wherein the interferon-α is Can be administered twice a day for several days. 20. A method according to any one of claims 14 to 17, The interferon-α can be administered one drop per hour for three days. 21. After retinal detachment surgery and/or vitrectomy, after trauma, and also in the anterior retinal abdomen. Diabetes mellitus in patients who require prevention of the formation of proliferative and proliferative vitreoretinopathy; As a result of retinal vascular disease, including blood clots, retinal vein occlusion, the preretinal membrane and proliferative vitreous A method for inhibiting the formation of systemic retinopathy, the method comprising: administering an effective amount to the vitreous body and retina of a patient; of interferon-α or interferon-α and a pharmacologically acceptable carrier. Administering a synthetic formulation for this method containing a body, a diluent and/or an excipient. Things that include things. 22. 22. A method according to claim 21, wherein interferon-α is ,000 to 5.0 x 106 IU/0.1 ml for intravitreal injection .